The sympathetic nervous system plays a key role in the development of hypertension, and elevated sympathetic activity is a major component of several cardiovascular risk factors, including stress. In addition, augmented cardiovascular sensitivity to acute stressors in young normotensive individuals predicts a higher risk of becoming hypertensive later in life, indicating that enhanced stress-responsiveness and long-term elevation of blood pressure (BP) are linked by the same, yet unidentified, stress-related central regulatory mechanisms. Here, we propose that brain-derived neurotrophic factor (BDNF), acting in the paraventricular nucleus of the hypothalamus (PVN), is a multi-faceted mechanism that is uniquely suited to directly activating PVN sympathoregulatory neurons to induce acute BP elevations to stress as well as mediating long-term transformation of the PVN neurocircuitry to facilitate responsiveness to hypertensive stimuli leading to the development of hypertension. Our recent publications and preliminary data suggest that BDNF exerts these effects in the PVN via mechanisms that have traditionally been recognized to mediate plasticity, learning and memory in hippocampal and cortical neuronal networks, but have not been explored in the PVN. These actions include 1) intracellular Ca2+-dependent BDNF expression in PVN neurons in response to excitatory input converging on the PVN during stress; 2) activation of the high-affinity BDNF receptor TrkB, leading to opening of the transient receptor potential channel-3 (TRPC3) via phospholipase C (PLC) signaling; 3) differential regulation of expression and function of N-methyl-D-aspartate (NMDA) and ?-aminobutyric acid type-A (GABAA) receptors, shifting the excitatory-inhibitory balance toward long-term sensitization in PVN sympathoregulatory neurons. In addition, there is evidence for important mechanisms that integrate actions of BDNF and angiotensin II (AngII), a key regulator of BP in the PVN. These newly discovered interactions are mediated by AngII-induced stimulation of BDNF expression; AngII-type-1 receptor (AT1R)-induced trans- activation of TrkB; and by BDNF-induced upregulation of AT1R. We employ a comprehensive array of in vitro patch-clamp and Ca2+-imaging techniques as well as in vivo experiments using viral vector-mediated genetic manipulation of BDNF signaling in rats to achieve the following aims: Aim 1: To elucidate TrkB?PLC?TRPC3- mediated mechanisms by which BDNF activates PVN sympathoregulatory neurons to acutely increase SNA and BP; Aim 2: To characterize functional interactions between BDNF and AngII in sympathoregulatory PVN neurons; and Aim 3: To determine how excessive activation of BDNF signaling augments excitatory and diminishes inhibitory synaptic function in PVN sympathoregulatory neurons to promote the development of hypertension. These studies have the strong potential to significantly advance the field by establishing BDNF as a highly important regulator of autonomic and cardiovascular function, one that mediates both acute stress responses and long-term adaptive mechanisms in the PVN leading to the development of hypertension.